The present invention relates to novel and pharmaceutically useful cycloalkylurea compounds or pharmaceutically acceptable salts thereof which inhibit acyl-CoA:cholesterol acyltransferase (ACAT) and are useful as hypolipidemic and anti-etherosclerotic medicines.
Hypercholesterolemia has been known to be a risk factor linked to lots of cardiovascular diseases. Increased level of plasma cholesterol may cause an accumulation of lipid-laden foam-cells at the artery wall, which is an early event in the development of atherosclerosis. Atherosclerosis would be the cause of many cardiovascular diseases including angina pectoris and myocardial infarction.
Cholesterol is esterified by microsomal acyl-CoA:cholesterol acyltransferase (hereinafter referred to as ACAT) in intestinal mucosa. The esters are then incorporated into chylomicrons, which are secreted into the plasma through the lymph. ACAT inhibitors would inhibit the esterification of free cholesterol in diet and bile. Consequently, they are expected to decrease the plasma cholesterol level by the suppression of the entry of cholesterol into the body pool.
Atherosclerosis is pathologically distinctive for the appearance with the accumulation of lipids, especially cholesterol esters, at the artery wall. It has been demonstrated that the accumulation of cholesteryl esters is largely mediated by the formation of lipid-laden foam cells derived from macrophages. Since intracellular free cholesterol is also esterified by ACAT in macrophages, ACAT inhibitors would decrease the accumulation of cholesteryl esters in the cells. Therefore they are expected to prevent the formation of foam cells and the progression of atherosclerosis.
Compounds having ACAT inhibitory activity are disclosed in the literature, for example, 3-(2,4-difluorophenyl)-1-[(4-(2,2-dimethylpropyl)phenyl)methyl]-1-(heptyl) urea in GB 2149394, 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide in U.S. Pat. No. 4,716,175 and so on. A variety of N-phenyl-N'-cycloalkylurea derivatives having ACAT inhibitory activity can be found in, for example, U.S. Pat. No. 4,387,105; EP-A-293880; EP-A-297610; EP-A-325397; EP-A-384320; EP-A-394422; and WO91/13871. Diphenylurea derivatives having ACAT inhibitory activity are also known in EP-A-405233. Further N-phenyl-N'-cycloalkylurea compounds are known in U.S. Pat. 3683001, U.S. Pat. No. 4,216,228 and GB 1028818, but they are disclosed only as being useful animal repellants, fungicides and herbicides, respectively.